Klepin, Heidi D.

Abstract Background We performed a prospective study evaluating a baseline GA battery and clinical outcomes in fit older adults (age ≥60 years) with AML and normal cardiac and renal function in the recent E-A NCTN E2906 phase 3 study. A patient-reported outcomes (PRO) assessment of Depression, Activities of Daily Living (ADL), Cognitive Function, Social Support (SS) domains, and comorbidity was performed at study registration to evaluate the prevalence of vulnerabilities and their impact on overall survival (OS) and 30-day induction mortality rates (IM) in this cohort selected for fitness to receive IC. Methods E2906 study design and results have been presented previously [n=727, age ≥60 years, randomized 1:1 to ‘standard 7&3‘ & high dose cytarabine (Arm A) vs. single agent clofarabine (CLO, Arm B), as remission induction (Step 1) and consolidation (Step 2)]. There was no difference in composite complete remission (CCR, 50%) or IM (8.5%), and CLO was inferior for OS. A baseline GA was a key secondary protocol objective, offered to all patients, and n=532 (73%) participated. We assessed Geriatric Depression Scale (GDS, none vs. any depressive symptoms, n=524); cognitive screen using Mini-Mental Exam Section (MMES, score 8/8 vs. <8, n=516); ADL & Instrumental ADL (iADL), (need for assistances vs. not n=526); a Medical Outcomes Study SS Survey (MOS-SS, measured as per unit increase, n=527); a Comorbidity survey ( ≤4 vs. ≥5 patient-reported comorbidities, n=530), patient-reported prescription medications use (PM, 0-3 vs. ≥4, n=519); and a survey of Sexual Desire (n=491) and Sexual Activity (n=477) within 4 weeks of AML diagnosis. Association of GA domains with OS, IM, and achievement of CCR was evaluated using the Chi-squared, Fisher's exact, and Wilcoxon rank sum test. Survival analysis was performed using the Cox proportional hazards models, adjusted for treatment arm. All p-values are 2-sided. Results The median age among those participating in GA battery was 67 yrs (range 60-85), including 38% age ≥70. There were 42% females, and ECOG performance status was 0 (28%), 1 (54%), 2 (16%), or 3 (2%). Central Cytogenetic review was classified (ELN2017) as Favorable (3%), Intermediate (66%), and Adverse (31%) risk. There was a notable rate of GA scores outside ‘normal’ clinical cutoff, including Depression (GDS 31%), cognitive and functional impairment [MMSE (37%), ADL (25%) and iADL (32%)], ≥5 Comorbidities (23%), and ≥4 PM's (44%). 81% & 76%, respectively, reported no sexual activity and low/none sexual desire. MOS-SS tended to be high in this cohort [mean (SD) score 87 (17)]. We observed a significant association of GA domains with OS & IM. For OS, absence of depressive symptoms [GDS, Hazard Ratio (HR) 0.79, 95% confidence Intervals (CI) 0.64-0.97, p=0.025)], MMES 8/8 (HR 0.78, 95%CI 0.64-0.96, p=0.016), requiring no assistance with ADLs (HR 0.65, 95%CI 0.52-0.82, p<0.001) and iADLs (HR 0.69, 95%CI 0.57-0.85, p<0.001), and ≤4 Comorbidities (HR 0.68, 95%CI 0.54-0.84, p=0.001) were significant for superior OS; use of ≥4 PM's was associated with inferior OS (HR 1.32, 95%CI 1.09-1.61, p=0.005). There was no association of sexual activity/desire, BMI ≥30 kg/m2, or MOS-SS with OS. IM was significantly higher among those with any depression symptoms (GDS, p=0.005), any ADL (p=0.010) or iADL (p=0.013) impairment, ≥5 comorbidities (p=0.037) and ≥4 PM's (p=0.001); there was no association with MOS-SS or MMES. There was no significant association of GA scores with cytogenetic risk group or with CCR rates. Only ADL independence (p=0.048), and possibly Comorbidity ≤4 (p=0.071), were associated with proceeding to Step 2. Conclusions In this large prospective cohort of fit older adults with AML selected to receive IC, we observed high rates of PRO-assessed GA vulnerability, which was significantly associated with inferior OS and higher IM rates, and (for ADL impairment) lower rates of proceeding to consolidation therapy. This suggests that functional and cognitive impairments are prevalent and can significantly impact outcome even in fit older adults. Despite potential long-term OS advantages of IC previously observed in E2906, efforts to systematically recognize those at higher risk based on GA PROs are needed to help identify patients who may be more appropriate for study of lower intensity treatment options to mitigate impact on IM and OS. SImilarly we plan to evaluate the potential benefit of GA-driven supportive care to improve patients' outcomes.

Background There is limited prospective or comparative data evaluating the HRQoL impact of intensive chemotherapy (IC) in older adults (age ≥60 years) with AML. In the recent EA E2906 phase 3 study of '7&3' (daunorubicin & cytarabine) vs. clofarabine (CLO), a putative lower intensity therapy, we incorporated a prospective patient-reported outcomes (PRO) assessment of HRQoL and fatigue to understand treatment impact from the patients' (pts) perspective. Methods E2906 study design and results have been presented previously [n=727, med. age 68 years (range 60-86), randomized 1:1 to ‘standard’ ‘7&3‘ & high dose cytarabine (Arm A) vs. single agent CLO (Arm B), as remission induction (Step 1) and consolidation (Step 2), respectively]. There was no difference in composite complete remission (CCR, 50%) or 30-day mortality rates (8.5%), and in primary analysis CLO was inferior for Overall Survival. HRQoL was a key secondary protocol endpoint. PROs assessed HRQoL and leukemia-specific symptoms and concerns using Functional Assessment of Cancer Therapy-Leukemia scale (FACT-Leu), & Fatigue using FACT-Fatigue subscale. PROs were administered at prespecified time points: (1) Baseline; (2) Cycle 1 at nadir (approx. Day 15); (3) End of Step 1 restaging (approx. D 40); (4) Beginning of Step 2 (1 st consolidation, approx. D 45); and (5) 2 nd cycle consolidation/End Step 2 (approx. D 60). The FACT-Leu Trial Outcome Index ( TOI) was calculated by summing physical well-being, functional well-being, and leukemia-specific concerns subscales to create a single composite score. Higher TOI scores correspond to better HRQoL. The primary endpoint was to evaluate TOI difference from randomization to day 30 after induction therapy between arms, evaluated using Wilcoxon rank sum test. We also compared Clinically Meaningful differences (CMiD) in TOI (defined as patient change ≥½ standard deviation from baseline TOI) between arms, using the X2 test. Pts not completing at least 2 assessment forms (including baseline) were excluded. Testing of constructs of Physical Well-being (PWB), Functional, Leukemia & Fatigue scales demonstrated high Cronbach's a values (a >0.7) except for PWB (a=0.672) at a single time point (End of Step 2). Results Baseline TOI was available for n=489, and 364 pts (n=182 each Arm) were evaluable in this planned analysis. Evaluating CMiD during Cycle 1 induction, pts in Arm B were less likely to experience ‘Worse’ TOI score (32% vs. 40.7%, Arm A), more likely to maintain stable TOI scores (49.1% vs. 39%, Arm A), and had a similar proportion of ‘Better’ TOI scores (20.3%, A vs. 18.9%, B) although differences were not significant (p=0.1389). Conversely in cycle 1 consolidation, more patients in Arm A experienced Better TOI (45.1% vs. 29.2%, Arm B), fewer had stable TOI (45.1% vs. 58.3%, Arm B), and rates of ‘Worse’ TOI were similar (9.8%, A vs 12.5%, Arm B), again differences were not significant (p=0.2616). There was no difference in Fatigue scores between Arms (p=0.49). We evaluated whether TOI and Fatigue scores could predict the ability to complete protocol therapy. In univariate analysis baseline TOI (p=0.0059) and Fatigue (p=0.0057) were associated with Step 1 completion, however on multivariate analysis (adjusting for age, sex, and Arm) were no longer significant [TOI, Odds Ratio (OR) 1.03 (0.98-1.08, p=0.27); Fatigue, OR 1.03 (0.96-1.11, p=0.42)]. There was a borderline association of TOI with Step 2 completion [TOI OR 1.10 (1.00-1.23, p=0.06)]. Using a multivariable linear mixed effects model, we observed similar and significant changes in TOI scores in both Arms, demonstrating the effect of IC & CLO on HRQoL (Figure). Comparing to baseline, TOI scores decreased significantly at C1 induction nadir (-4.0873, p<0.0001), and increased by 5.0762 (p=0.0004) at end Step 1, by 6.9047 at cycle 1 consolidation (p<0.0001), and by 11.4601 (p<0.0001) at end Step 2. Differences were mainly apparent in those who achieved CCR, and there was significant attrition in PRO responses in non-CCR pts. Conclusions Older adults experienced significant improvement in HRQoL after nadir regardless of therapy, and those achieving CCR report significantly higher scores. We did not observe differences in leukemia specific HRQoL or fatigue between treatment Arms (7&3 vs. CLO). Patient-reported HRQoL & Fatigue was not predictive of completion of protocol therapy. These results serve as a benchmark for expectations with IC in older adults.

PURPOSE: Clinical trials are important for managing older patients with AML. We investigated differences in outcomes of older patients with AML on the basis of whether patients participated in intensive chemotherapy trials at community versus academic cancer centers. METHODS: We used data from the Alliance for Clinical Trials in Oncology phase III trials that enrolled patients age ≥ 60 years with newly diagnosed AML between 1998 and 2002 in the Cancer and Leukemia Group B (CALGB) 9720 trial and between 2004 and 2006 in the CALGB 10201 trial. Centers funded by the NCI Community Oncology Research Program were identified as community cancer centers; others were designated as academic cancer centers. Logistic regression models and Cox proportional hazards models were used to compare 1-month mortality and overall survival (OS) by center type. RESULTS: Seventeen percent of the 1,170 patients were enrolled in clinical trials in community cancer centers. The study results demonstrated comparable rates of grade ≥3 adverse events (97% v 93%), 1-month mortality (19.1% v 16.1%), and OS (43.9% v 35.7% at 1 year) between community versus academic cancer centers, respectively. After adjusting for covariates, 1-month mortality (odds ratio, 1.40; 95% CI, 0.92 to 2.12; P = .11) and OS (hazard ratio, 1.04; 95% CI, 0.88 to 1.22; P = .67) were not statistically different among patients treated in community versus academic cancer centers. CONCLUSION: An older patient population, who have complex health care needs, can be successfully treated on intensive chemotherapy trials in select community cancer centers with outcomes comparable with that achieved at academic cancer centers.

AbstractAlthough adults aged 65 years or older make up a strong majority of cancer patients, their underrepresentation in cancer clinical trials leads to the lack of representative data to guide evidence-based therapeutic decisions in this patient population. The Trial Design Working Group, convened as part of the workshop titled, Engaging Older Adults in the National Cancer Institute Clinical Trials Network: Challenges and Opportunities, recommended study designs and design elements that could improve accrual of older adults in National Cancer Institute–funded clinical trials. These include trials that are specifically designed to enroll older adults, trials that include a cohort of older patients (parallel cohort, stratified cohort, or embedded cohort), and trials with pragmatic design elements to facilitate enrollment of older adults. This manuscript provides brief descriptions of the recommended designs, examples of successful trials, and considerations for implementation of these designs.As with any clinical trial, the scientific questions and trial objectives should drive the study design, the selection of endpoints and intervention, and eligibility criteria. When designing trials that include older adults, the heterogeneity of fitness levels is an important consideration as fitness can influence accrual rates and outcomes. Appropriately incorporating geriatric assessments can help identify the optimal subset of older patients for inclusion and minimize selection bias. Incorporating pragmatic design elements to reduce the burden on trial participants as well as on accruing sites and retaining essential elements to ensure that the main goal of the trial can be accomplished can enhance enrollment without compromising the integrity of trials.

AbstractTo improve the care of older adults with cancer, the traditional approach to clinical trial design needs to be reconsidered. Older adults are underrepresented in clinical trials with limited or no information on geriatric-specific factors, such as cognition or comorbidities. To address this knowledge gap and increase relevance of therapeutic clinical trial results to the real-life population, integration of aspects relevant to older adults is needed in oncology clinical trials. Geriatric assessment (GA) is a multidimensional tool comprising validated measures assessing specific health domains that are more frequently affected in older adults, including aspects related to physical function, comorbidity, medication use (polypharmacy), cognitive and psychological status, social support, and nutritional status. There are several mechanisms for incorporating either the full GA or specific GA measures into oncology therapeutic clinical trials to contribute to the overarching goal of the trial. Mechanisms include utilizing GA measures to better characterize the trial population, define trial eligibility, allocate treatment receipt within the context of the trial, develop predictive models for treatment outcomes, guide supportive care strategies, personalize care delivery, and assess longitudinal changes in GA domains. The objective of this manuscript is to review how GA measures can contribute to the overall goal of a clinical trial, to provide a framework to guide the selection and integration of GA measures into clinical trial design, and ultimately enable accrual of older adults to clinical trials by facilitating the design of trials tailored to older adults treated in clinical practice.

12040 Background: Novel strategies are needed to assess frailty in the context of therapy decisions for older adults with acute myeloid leukemia (AML). Our objectives were to describe pre-treatment DAFI scores for older AML patients treated on clinical trials and explore their relationship with treatment outcomes. Methods: We conducted a exploratory analysis utilizing data from two clinical trials of adults aged ≥60 years with newly diagnosed AML (Alliance/CALGB 11001 [intensive therapy] and Alliance/CALGB 11002 [non-intensive therapy]). We included the subset of patients in each trial enrolled on geriatric assessment companion studies (Alliance/CALGB 361006, 361101). A DAFI score was calculated for each patient using 51 variables including demographic, geriatric assessment, and laboratory data derived from the geriatric assessment. Individuals with ≥90% items were included (consistent with other studies); DAFI scores ranged from 0 to 1 and were evaluated using established categories (0- <.2 [robust]; 0.2-<.35 [pre-frail]; 0.35+ [frail]) and as a continuous score. Associations between DAFI scores and toxicity and overall survival (OS) were evaluated with Fisher’s exact-testing and Kaplan Meier/cox proportional hazards, respectively. Results: The median age was 68 years (range 61, 82) and 72 years (range 61, 92) for those getting intensive (N=31) and less intensive therapy (N= 75), respectively. Individuals in the intensive study had a median pre-treatment DAFI score of 0.15 (range 0.05, 0.31) and were all categorized as robust (75%) or pre-frail (25%). There was no significant difference in median OS (14.6 vs. 14.7 months) or non-hematological grade 3+ adverse events (AEs; 85% vs. 89%) between robust vs. pre-frail individuals in this trial, respectively. However, pre-frail adults experienced a trend towards greater grade 4 non-hematological toxicity than robust individuals (67% vs 26%, p=0.05). In the non-intensive trial, the median DAFI score was 0.24 (range 0.04, 0.48) and most individuals were pre-frail (49.3%) or frail (17.3%). Non-hematologic grade 3+ AEs did not vary by DAFI group, 88% robust, 95% pre-frail, and 77% frail (p=0.15). Median OS was 7.4, 10.8, and 6.3 months for robust, pre-frail, and frail respectively (p=0.17). Adjusting for age, each 0.1 increase in DAFI score was associated with increased mortality hazard (HR 1.8, 95% CI 1.0-3.2). Conclusions: DAFI score calculation provides a potential novel strategy for categorization of frailty in AML. In our assessment, higher DAFI scores were associated with toxicity during intensive induction and mortality in the less intensive setting. This method should be studied in larger samples randomized by treatment intensity. Support: UG1CA189823; Bayer Healthcare/Berlex (CALGB 11001); NCT01253070 (CALGB 11001). Clinical trial information: NCT01253070, NCT01420926.

Abstract Geriatric assessment (GA) predicts survival among older adults with acute myeloid leukemia (AML) treated intensively. We evaluated the predictive utility of GA among older adults treated with low-intensity therapy on a multisite trial. We conducted a companion study (CALGB 361101) to a randomized phase 2 trial (CALGB 11002) of adults ≥60 years and considered “unfit” for intensive therapy, testing the efficacy of adding bortezomib to decitabine therapy. On 361101, GA and quality of life (QOL) assessment was administered prior to treatment and every other subsequent cycle. Relationships between baseline GA and QOL measures with survival were evaluated using Kaplan-Meier estimation and Cox proportional hazards models. One-hundred sixty-five patients enrolled in CALGB 11002, and 96 (52%) of them also enrolled in 361101 (median age, 73.9 years). Among participants, 85.4% completed ≥1 baseline assessment. In multivariate analyses, greater comorbidity (hematopoietic cell transplantation-specific comorbidity index &gt;3), worse cognition (Blessed Orientation-Memory-Concentration score &gt;4), and lower European Organization for Research and Treatment of Cancer global QOL scores at baseline were significantly associated with shorter overall survival (P &lt; .05 each) after adjustment for Karnofsky Performance Status, age, and treatment arm. Dependence in instrumental activities of daily living and cognitive impairment were associated with 6-month mortality (hazard ratio [HR], 3.5; confidence interval [CI], 1.2-10.4; and HR, 3.1; CI, 1.1-8.6, respectively). GA measures evaluating comorbidity, cognition, and self-reported function were associated with survival and represent candidate measures for screening older adults planned to receive lower-intensity AML therapies. This trial was registered at www.clinicaltrials.gov as #NCT01420926 (CALGB 11002).

Abstract Cancer is a disease of aging and, as the world's population ages, the number of older persons with cancer is increasing and will make up a growing share of the oncology population in virtually every country. Despite this, older patients remain vastly underrepresented in research that sets the standards for cancer treatments. Consequently, most of what we know about cancer therapeutics is based on clinical trials conducted in younger, healthier patients, and effective strategies to improve clinical trial participation of older adults with cancer remain sparse. For this systematic review, the authors evaluated published studies regarding barriers to participation and interventions to improve participation of older adults in cancer trials. The quality of the available evidence was low and, despite a literature describing multifaceted barriers, only one intervention study aimed to increase enrollment of older adults in trials. The findings starkly amplify the paucity of evidence‐based, effective strategies to improve participation of this underrepresented population in cancer trials. Within these limitations, the authors provide their opinion on how the current cancer research infrastructure must be modified to accommodate the needs of older patients. Several underused solutions are offered to expand clinical trials to include older adults with cancer. However, as currently constructed, these recommendations alone will not solve the evidence gap in geriatric oncology, and efforts are needed to meet older and frail adults where they are by expanding clinical trials designed specifically for this population and leveraging real‐world data.

The coronavirus disease 2019 (COVID-19) pandemic has disrupted all aspects of clinical care, including cancer clinical trials. In March 2020, ASCO launched a survey of clinical programs represented on its Cancer Research Committee and Research Community Forum Steering Group and taskforces to learn about the types of changes and challenges that clinical trial programs were experiencing early in the pandemic. There were 32 survey respondents; 14 represented academic programs, and 18 represented community-based programs. Respondents indicated that COVID-19 is leading programs to halt or prioritize screening and/or enrollment for certain clinical trials and cease research-only visits. Most reported conducting remote patient care where possible and remote visits and monitoring with sponsors and/or contract research organizations (CROs); respondents viewed this shift positively. Numerous challenges with conducting clinical trials were reported, including enrollment and protocol adherence difficulties with decreased patient visits, staffing constraints, and limited availability of ancillary services. Interactions with sponsors and CROs about modifying trial procedures were also challenging. The changes in clinical trial procedures identified by the survey could serve as strategies for other programs attempting to maintain their clinical trial portfolios during the COVID-19 pandemic. Additionally, many of the adaptations to trials made during the pandemic provide a long-term opportunity to improve and transform the clinical trial system. Specific improvements could be expanded use of more pragmatic or streamlined trial designs, fewer clinical trial–related patient visits, and minimized sponsor and CRO visits to trial programs.